tbuckley/cabot-search huggingface dataset:
Early Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial—MIST-3
Authors: Eihab O. Bedawi, Dionisios Stavroulias, Emma Hedley, Kevin G. Blyth, Alan Kirk, Duneesha De Fonseka, John G. Edwards, Eveline Internullo, John P. Corcoran, Adrian Marchbank, Rakesh Panchal, Edward Caruana, Owais Kadwani, Lawrence Okiror, Tarek Saba, Manoj Purohit, Rachel M. Mercer, Rhona Taberham, Nikolaos Kanellakis, Alison M. Condliffe, Leon G. Lewis, Dinesh N. Addala, Rachelle Asciak, Radhika Banka, Vineeth George, Maged Hassan, David McCracken, Anand Sundaralingam, John M. Wrightson, Melissa Dobson, Alex West, Graham Barnes, John Harvey, Mark Slade, Mae Chester-Jones, Susan Dutton, Robert F. Miller, Nick A. Maskell, Elizabeth Belcher, Najib M. Rahman
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized controlled trial (RCT). Objectives: To establish the feasibility of randomization in a surgery versus non-surgery trial as well as the key outcome measures which are important to identify relevant patient-centered outcomes in a RCT. Methods: MIST-3 was a prospective multicenter RCT. All-comers with a confirmed diagnosis of pleural infection were enrolled and those with ongoing pleural sepsis after up to 24-hours of standard care were randomized to one of 3 arms; continued standard care, IET, or surgical opinion for VATS. The analysis was by intention to treat, despite some participants in the VATS arm not being fit enough to undergo surgical intervention. Main Results: Of 97 eligible patients, 60 (62%) participants were randomized. Despite a difference in time-to-intervention, length of stay was similar in both arms. There were no significant inter-group differences in 2-month readmission and further intervention. Compared to VATS, IET demonstrated a greater improvement in mean EQ-5D-5L health utility index at 2 months from baseline. Conclusion: This is the first multicenter RCT of early IET vs early surgery in pleural infection. Despite logistical challenges posed by the COVID-19 pandemic, the study met its predefined feasibility criteria. Potential shortening of LOS with early surgery, and signals toward earlier resolution of pain and shortened recovery with IET were demonstrated. The study findings suggest that a definitive study is feasible and required to assess optimal initial management. Clinical trial registration available at www.isrctn.com, ID: ISRCTN18192121. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)
Adolescent and Young Adult Germ Cell Tumors: Epidemiology, Genomics, Treatment, and Survivorship
Authors: Lois B. Travis, Darren R. Feldman, Chunkit Fung, Jenny N. Poynter, Michelle Lockley, A. Lindsay Frazier
Journal: Journal of Clinical Oncology (2023)

Innovations in the care of adolescent and young adult (AYA) germ cell tumors (GCTs) are needed for one of the most common AYA cancers for which treatment has not significantly changed for several decades. Testicular GCTs (TGCTs) are the most common cancers in 15- to 39-year-old men, and ovarian GCTs (OvGCTs) are the leading gynecologic malignancies in women younger than 25 years. Excellent outcomes, even in widely metastatic disease using cisplatin-based chemotherapy, can be achieved since Einhorn and Donohue's landmark 1977 study in TGCT. However, as the severity of accompanying late effects (ototoxicity, neurotoxicity, cardiovascular disease, second malignant neoplasms, nephrotoxicity, and others) has emerged, efforts to deintensity treatment and find alternatives to cisplatin have taken on new urgency. Current innovations include the collaborative design of clinical trials that accrue GCTs across all ages and both sexes, including adolescents (previously on pediatric trials), and OvGCT (previously on gynecologic-only trials). Joint trials accrue larger sample sizes at a faster rate and therefore evaluate new approaches more rapidly. These joint trials also allow for biospecimen collection to further probe GCT etiology and underlying mechanisms of tumor growth, thus providing new therapeutic options. This AYA approach has been fostered by The Malignant Germ Cell International Consortium, which includes over 115 GCT disease experts from pediatric, gynecologic, and genitourinary oncologies in 16 countries. Trials in development incorporate, to our knowledge, for the first time, molecular risk stratification and precision oncology approaches on the basis of specific GCT biology. This collaborative AYA approach pioneering successfully in GCT could serve as a model for impactful research for other AYA cancer types.
SynCLay: Interactive synthesis of histology images from bespoke cellular layouts
Authors: Srijay Deshpande, Muhammad Dawood, Fayyaz Minhas, Nasir Rajpoot
Journal: Medical Image Analysis (2023)

Automated synthesis of histology images has several potential applications in computational pathology. However, no existing method can generate realistic tissue images with a bespoke cellular layout or user-defined histology parameters. In this work, we propose a novel framework called SynCLay (Synthesis from Cellular Layouts) that can construct realistic and high-quality histology images from user-defined cellular layouts along with annotated cellular boundaries. Tissue image generation based on bespoke cellular layouts through the proposed framework allows users to generate different histological patterns from arbitrary topological arrangement of different types of cells (e.g., neutrophils, lymphocytes, epithelial cells and others). SynCLay generated synthetic images can be helpful in studying the role of different types of cells present in the tumor microenvironmet. Additionally, they can assist in balancing the distribution of cellular counts in tissue images for designing accurate cellular composition predictors by minimizing the effects of data imbalance. We train SynCLay in an adversarial manner and integrate a nuclear segmentation and classification model in its training to refine nuclear structures and generate nuclear masks in conjunction with synthetic images. During inference, we combine the model with another parametric model for generating colon images and associated cellular counts as annotations given the grade of differentiation and cellularities (cell densities) of different cells. We assess the generated images quantitatively using the Frechet Inception Distance and report on feedback from trained pathologists who assigned realism scores to a set of images generated by the framework. The average realism score across all pathologists for synthetic images was as high as that for the real images. Moreover, with the assistance from pathologists, we showcase the ability of the generated images to accurately differentiate between benign and malignant tumors, thus reinforcing their reliability. We demonstrate that the proposed framework can be used to add new cells to a tissue images and alter cellular positions. We also show that augmenting limited real data with the synthetic data generated by our framework can significantly boost prediction performance of the cellular composition prediction task. The implementation of the proposed SynCLay framework is available at https://github.com/Srijay/SynCLay-Framework.
Advancing Diagnostics and Therapy to Reach Universal Cure in Childhood ALL
Authors: Rob Pieters, Charles G. Mullighan, Stephen P. Hunger
Journal: Journal of Clinical Oncology (2023)

Systemic combination chemotherapy and intrathecal chemotherapy markedly increased the survival rate of children with ALL. In the past two decades, the use of minimal (measurable) residual disease (MRD) measurements early in therapy improved risk group stratification with subsequent treatment intensifications for patients at high risk of relapse, and enabled a reduction of treatment for low-risk patients. The recent development of more sensitive MRD technologies may further affect risk stratification. Molecular genetic profiling has led to the discovery of many new subtypes and their driver genetic alterations. This increased our understanding of the biological basis of ALL, improved risk classification, and enabled implementation of precision medicine. In the past decade, immunotherapies, including bispecific antibodies, antibody-drug conjugates, and cellular therapies directed against surface proteins, led to more effective and less toxic therapies, replacing intensive chemotherapy courses and allogeneic stem-cell transplantation in patients with relapsed and refractory ALL, and are now being tested in newly diagnosed patients. It has taken 50-60 years to increase the cure rate in childhood ALL from 0% to 90% by stepwise improvements in chemotherapy. This review provides an overview of how the developments over the past 10-15 years mentioned above have significantly changed the diagnostic and treatment approach in ALL, and discusses how the integrated use of molecular and immunotherapeutic insights will very likely direct efforts to cure those children with ALL who are not cured today, and improve the quality of life for survivors who should have decades of life ahead. Future efforts must focus on making effective, yet very expensive, new technologies and therapies available to children with ALL worldwide.
An entropy weight method to integrate big omics and mechanistically evaluate DILI
Authors: Yuan Jin, Yingqing Shou, Qinkai Lei, Chenlong Du, Lin Xu, Ningning Chen, Wanli Ma, Xiaoxiao Zhu, Shuya Zhou, Yuxin Zheng, Dianke Yu
Journal: Hepatology (2023)

Background and Aims: DILI accounts for more than half of acute liver failure cases in the United States and is a major health care issue for the public worldwide. As investigative toxicology is playing an evolving role in the pharmaceutical industry, mechanistic insights into drug hepatotoxicity can facilitate drug development and clinical medication. Methods: By integrating multisource datasets including gene expression profiles of rat livers from open TG-GATE database and DrugMatrix, drug labels from FDA Liver Toxicity Knowledge Base, and clinical reports from LiverTox, and with the employment of bioinformatic and computational tools, this study developed an approach to characterize and predict DILI based on the molecular understanding of the processes (toxicity pathways). Results: A panel of 11 pathways widely covering biological processes and stress responses was established using a training set of six positive and one negative DILI drugs from open TG-GATEs. An entropy weight method-based model was developed to weight responsive genes within a pathway, and an interpretable machine-learning (ML) model XGBoot-SHAP was trained to rank the importance of pathways to the panel activity. The panel activity was proven to differentiate between injured and noninjured sample points and characterize DILI manifestation using six training drugs. Next, the model was tested using an additional 89 drugs (61 positives + 28 negatives), and a precision of 86% and higher can be achieved. Conclusions: This study provides a novel approach to mechanisms-driven prediction modeling, as well as big data integration for insights into pharmacology and other human biology areas.
NanoIEA: A Nanopatterned Interdigitated Electrode Array‐Based Impedance Assay for Real‐Time Measurement of Aligned Endothelial Cell Barrier Functions
Authors: Jong Seob Choi, Hyun Myung Doo, Byunggik Kim, Su Han Lee, Sang‐keun Sung, Gwangjun Go, Allister Suarez, Yeseul Kim, Byung Mook Weon, Byung‐Ok Choi, Hyung Jin Kim, Deok‐Ho Kim
Journal: Advanced Healthcare Materials (2023)

A nanopatterned interdigitated electrode array (nanoIEA)-based impedance assay is developed for quantitative real-time measurement of aligned endothelial cell (EC) barrier functions in vitro. A bioinspired poly(3,4-dihydroxy-L-phenylalanine) (poly (l-DOPA)) coating is applied to improve the human brain EC adhesion onto the Nafion nanopatterned surfaces. It is found that a poly (l-DOPA)-coated Nafion grooved nanopattern makes the human brain ECs orient along the nanopattern direction. Aligned human brain ECs on Nafion nanopatterns exhibit increased expression of genes encoding tight and adherens junction proteins. Aligned human brain ECs also have enhanced impedance and resistance versus unaligned ones. Treatment with a glycogen synthase kinase-3 inhibitor (GSK3i) further increases impedance and resistance, suggesting synergistic effects occur on the cell-cell tightness of in vitro human brain ECs via a combination of anisotropic matrix nanotopography and GSK3i treatment. It is found that this enhanced cell-cell tightness of the combined approach is accompanied by increased expression of claudin protein. These data demonstrate that the proposed nanoIEA assay integrated with poly (l-DOPA)-coated Nafion nanopatterns and interdigitated electrode arrays can make not only biomimetic aligned ECs, but also enable real-time measurement of the enhanced barrier functions of aligned ECs via tighter cell-cell junctions.
Global variations in lung cancer incidence by histological subtype in 2020: a population-based study
Authors: Yanting Zhang, Salvatore Vaccarella, Eileen Morgan, Mengmeng Li, Jaione Etxeberria, Eric Chokunonga, Shyam Shunker Manraj, Bakarou Kamate, Abidemi Omonisi, Freddie Bray
Journal: The Lancet Oncology (2023)
CYP8B1 downregulation mediates the metabolic effects of vertical sleeve gastrectomy in mice
Authors: Yanjun Liu, Jui Tu, Linsen Shi, Zhipeng Fang, Mingjie Fan, Jianying Zhang, Lili Ding, Yiqiang Chen, Yangmeng Wang, Eryun Zhang, Senlin Xu, Nisha Sharma, John D. Gillece, Lauren J. Reining, Lihua Jin, Wendong Huang
Journal: Hepatology (2023)

Background and Aims: Although the benefits of vertical sleeve gastrectomy (VSG) surgery are well known, the molecular mechanisms by which VSG alleviates obesity and its complications remain unclear. We aim to determine the role of CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) in mediating the metabolic benefits of VSG. Approach and Results: We found that expression of CYP8B1, a key enzyme in controlling the 12α-hydroxylated (12α-OH) bile acid (BA) to non-12α-OH BA ratio, was strongly downregulated after VSG. Using genetic mouse models of CYP8B1 overexpression, knockdown, and knockout, we demonstrated that overexpression of CYP8B1 dampened the metabolic improvements associated with VSG. In contrast, short hairpin RNA–mediated CYP8B1 knockdown improved metabolism similar to those observed after VSG. Cyp8b1 deficiency diminished the metabolic effects of VSG. Further, VSG-induced alterations to the 12α-OH/non-12α-OH BA ratio in the BA pool depended on CYP8B1 expression level. Consequently, intestinal lipid absorption was restricted, and the gut microbiota (GM) profile was altered. Fecal microbiota transplantation from wild type-VSG mice (vs. fecal microbiota transplantation from wild-type–sham mice) improved metabolism in recipient mice, while there were no differences between mice that received fecal microbiota transplantation from knockout-sham and knockout-VSG mice. Conclusions: CYP8B1 is a critical downstream target of VSG. Modulation of BA composition and gut microbiota profile by targeting CYP8B1 may provide novel insight into the development of therapies that noninvasively mimic bariatric surgery to treat obesity and its complications.
Laser‐Assisted Structuring of Graphene Films with Biocompatible Liquid Crystal Polymer for Skin/Brain‐Interfaced Electrodes
Authors: Rowoon Park, Dong Hyeon Lee, Chin Su Koh, Young Woo Kwon, Seon Yeong Chae, Chang‐Seok Kim, Hyun Ho Jung, Joonsoo Jeong, Suck Won Hong
Journal: Advanced Healthcare Materials (2023)

The work presented here introduces a facile strategy for the development of flexible and stretchable electrodes that harness the robust characteristics of carbon nanomaterials through laser processing techniques on a liquid crystal polymer (LCP) film. By utilizing LCP film as a biocompatible electronic substrate, control is demonstrated over the laser irradiation parameters to achieve efficient pattern generation and transfer printing processes, thereby yielding highly conductive laser-induced graphene (LIG) bioelectrodes. To enhance the resolution of the patterned LIG film, shadow masks are employed during laser scanning on the LCP film surface. This approach is compatible with surface-mounted device integration, enabling the circuit writing of LIG/LCP materials in a flexible format. Moreover, kirigami-inspired on-skin bioelectrodes are introduced that exhibit reasonable stretchability, enabling independent connections to healthcare hardware platforms for electrocardiogram (ECG) and electromyography (EMG) measurements. Additionally, a brain-interfaced LIG microelectrode array is proposed that combines mechanically compliant architectures with LCP encapsulation for stimulation and recording purposes, leveraging their advantageous structural features and superior electrochemical properties. This developed approach offers a cost-effective and scalable route for producing patterned arrays of laser-converted graphene as bioelectrodes. These bioelectrodes serve as ideal circuit-enabled flexible substrates with long-term reliability in the ionic environment of the human body.
Noncanonical regulation of HOIL-1 on cancer stemness and sorafenib resistance identifies pixantrone as a novel therapeutic agent for HCC
Authors: Peng Chen, Zheyu Dong, Wei Zhu, Junling Chen, Yuxin Zhou, Qiuyue Ye, Xinxin Liao, Yongfa Tan, Chuanjiang Li, Yuhao Wang, Huajin Pang, Chunhua Wen, Yuchuan Jiang, Xiaoqing Li, Bo Li, Aihetaimu Aimaier, Li Lin, Jian Sun, Jiajie Hou, Libo Tang, Jinlin Hou, Yongyin Li
Journal: Hepatology (2023)

Cancer stem cells (CSCs) contribute to therapy resistance in HCC. Linear ubiquitin chain assembly complex (LUBAC) has been reported to accelerate the progression of cancers, yet its role in the sorafenib response of HCC is poorly defined. Herein, we investigated the impact of LUBAC on sorafenib resistance and the CSC properties of HCC, and explored the potential targeted drugs.
The forgotten girls: the state of evidence for health interventions for pregnant adolescents and their newborns in low-income and middle-income countries
Authors: Farnaz Sabet, Audrey Prost, Sadaf Rahmanian, Heba Al Qudah, Mauro Nogueira Cardoso, John B Carlin, Susan M Sawyer, George C Patton
Journal: The Lancet (2023)
Defining access without excess: expanding appropriate use of antibiotics targeting multidrug-resistant organisms
Authors: Twisha S Patel, Hatim Sati, Fernanda C Lessa, Payal K Patel, Arjun Srinivasan, Lauri A Hicks, Melinda M Neuhauser, Deborah Tong, Maarten van der Heijden, Solange C Alves, Haileyesus Getahun, Benjamin J Park
Journal: The Lancet Microbe (2023)

Antimicrobial resistance remains a significant global public health threat. Although development of novel antibiotics can be challenging, several new antibiotics with improved activity against multidrug-resistant Gram-negative organisms have recently been commercialised. Expanding access to these antibiotics is a global public health priority that should be coupled with improving access to quality diagnostics, health care with adequately trained professionals, and functional antimicrobial stewardship programmes. This comprehensive approach is essential to ensure responsible use of these new antibiotics.
Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma
Authors: Kavita Y. Sarin, John Kincaid, Brittney Sell, Jahanbanoo Shahryari, Matthew A. J. Duncton, Elaine Morefield, Wenchao Sun, Karol Prieto, Omar Chavez-Chiang, Carlos de Moran Segura, Jonathan Nguyen, Roderick T. Bronson, Scott R. Plotkin, Gerd G. Kochendoerfer, Peter Fenn, Michael A. Wootton, Christopher Powala, Mark P. de Souza, Kenneth Y. Tsai
Journal: Science Translational Medicine (2023)

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.
Donor-derived regulatory dendritic cell infusion modulates effector CD8 <sup>+</sup> T cell and NK cell responses after liver transplantation
Authors: Lillian M. Tran, Camila Macedo, Alan F. Zahorchak, Xinyan Gu, Beth Elinoff, Aatur D. Singhi, Brian Isett, Adriana Zeevi, Megan Sykes, Kevin Breen, Avantika Srivastava, Erin M. Ables, Douglas Landsittel, Mindi A. Styn, Abhinav Humar, Fadi G. Lakkis, Diana M. Metes, Angus W. Thomson
Journal: Science Translational Medicine (2023)

Immune cell–based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant. Thirteen patients were given a single infusion of donor-derived DCreg 1 week before transplant (STUDY) and were compared with 40 propensity-matched standard-of-care (SOC) patients. Donor-derived DCreg infusion was well tolerated in all STUDY patients. There were no differences in postoperative complications or biopsy-confirmed acute rejection compared with SOC patients up to 12M. DCreg administration was associated with lower frequencies of effector T-bet + Eomes + CD8 + T cells and CD16 bright natural killer (NK) cells and an increase in putative tolerogenic CD141 + CD163 + DCs compared with SOC at 12M. Antidonor proliferative capacity of interferon-γ + (IFN-γ + ) CD4 + and CD8 + T cells was lower compared with antithird party responses in STUDY participants, but not in SOC patients, at 12M. In addition, lower circulating concentrations of interleukin-12p40 (IL-12p40), IFN-γ, and CXCL10 were detected in STUDY participants compared with SOC patients at 12M. Analysis of 12M allograft biopsies revealed lower frequencies of graft-infiltrating CD8 + T cells, as well as attenuation of cytolytic T H 1 effector genes and pathways among intragraft CD8 + T cells and NK cells, in DCreg-infused patients. These reductions may be conducive to reduced dependence on immunosuppressive drug therapy or immunosuppression withdrawal.